Intraperitoneal Drug Delivery Research Articles

Mucoadhesive hybrid gel improves intraperitoneal platinum delivery

A leading cause of death and suffering in patients with abdominal or pelvic malignancies is progression of peritoneal surface disease. Changes in the use of chemotherapy have shown significant survival benefits for intraperitoneal or combined intraperitoneal and intravenous treatment following optimal surgical cytoreduction. However, broader clinical use of intraperitoneal therapy has not reached its full potential due to limited efficacy, accessibility and nonspecific toxicity. To overcome these problems, we developed a mucoadhesive hybrid gel (HG) for a local, intraperitoneal drug delivery. In vivo studies confirmed reliable adherence and residence of the gel to the peritoneal sidewall for at least 72 h exhibiting no signs of tissue toxicity. Functionally active CDDP was released from HG within 2h and was equal to free CDDP in vitro. Moreover, intraperitoneal application of HG-CDDP significantly enhanced CDDP accumulation in the genomic DNA of peritoneal tissues compared to the same CDDP dose administered intravenously. These findings indicate the potential application of this hybrid gel as a mucoadhesive drug carrier amendable to use for intraperitoneal drug delivery and possible expansion for use on other mucosal surfaces of the female reproductive tract.

Optimization of Drug Delivery Systems for Intraperitoneal Therapy to Extend the Residence Time of the Chemotherapeutic Agent

Intraperitoneal (IP) chemotherapy is an effective way of treating peritoneal carcinomatosis of colorectal origin after complete cytoreduction. Although IP therapy has been already performed for many years, no standardized treatment design has been developed in terms of schedule, residence time, drug, or carrier solution. Because of the fast clearance of the conventional intravenous (IV) drug delivery systems used for IP therapy, a lot of research is performed to optimize IP drug delivery and extend the residence time of the cytotoxic agent in the peritoneal cavity. This paper reviews the recent advances made in drug delivery systems for IP chemotherapy, discussing the use of microparticles, nanoparticles, liposomes, micelles, implants, and injectable depots for IP delivery.

Description of a novel approach for intraperitoneal drug delivery and the related device

Two significant limitations of intraperitoneal drug therapy are limited drug distribution and poor penetration into peritoneal nodules. A possible solution is the application of the so-called "therapeutic pneumoperitoneum," taking advantage of the gaseous nature and the pressure of capnoperitoneum during laparoscopy. Our objective was to develop a device able to apply such therapeutic pneumoperitoneum. The technology presented here is a spraying device and can be introduced through a trocar. It is driven by mechanical pressure and consists of an injector, a line, and a nozzle. An in vivo experimental study was performed in five pigs. A transvaginal cholecystectomy was performed. At the end of the procedure, a standard dose of methylene blue was sprayed/infused into the abdominal cavity for 30 min (4 test animals w/therapeutic pneumoperitoneum (12 mmHg CO(2)) and 1 control animal w/conventional lavage (2 l intra-abdominal volume with extracorporeal circulation)). At the end of the procedure, all animals were autopsied and the peritoneum was analyzed. Outcome criteria were: (1) drug distribution (as assessed by the stained peritoneal surface at autopsy), and (2) diffusion into the peritoneum (presence or not of macroscopic staining of the outer aspect of the peritoneum immediately after surgery). Stained peritoneal surface was larger after aerosol application compared with peritoneal lavage, and staining more intense. Hidden peritoneal surfaces and the anterior abdominal wall were stained only in the aerosol group. In contrast to peritoneal lavage, the outer aspect of peritoneal membrane was immediately stained after pressurized spraying. This device and the related approach significantly improve both distribution and penetration of a test substance into the peritoneal cavity in a large animal model. This might be a significant progress in treating intraperitoneal disease, in particular peritoneal carcinomatosis.

Abstract 1948: Tissue accumulation and release of platinum from a novel chitosan-hybrid gel after intraperitoneal drug delivery

Abstract Gynecological malignancies such as cervical, endometrial and ovarian cancer still are the leading causes of death for women worldwide. However, standard therapies such as surgical cytoreduction and systemic chemotherapy combined with radiation have shown limited-efficacy by accessibility as well as nonspecific toxicity. To overcome those limitations, we previously reported about the development of a muco-adhesive, chitosan-hybrid gel (CS(BCDDP)) embedded with alginate beads containing cisplatin (CDDP) for a local, intraperitoneal application (# 3232, AACR 2011). Here we report the results of CDDP release from the (CS(BCDDP)), its cellular activity in vitro and CDDP accumulation to genomic DNA (gDNA) of tissues in vivo. To determine the amount of CDDP released from (CS(BCDDP)) in vitro, we used a colorimetric SnCl2 assay following the incubation in 0.9% NaCl solution for 24 hrs. (CS(BCDDP)) demonstrated successful release of 90% CDDP within 2 hrs and consistent CDDP-release could be maintained for up to 24 hrs. To test activity of CDDP released from (CS(BCDDP)), clonogenic assay was performed with Hela (human cervical adenocarcinoma) cells. Cells treated with (CS(BCDDP)) demonstrated a significantly low number of colonies, generating 9 (± 6) colonies per 500 cells seeded compared with 233 (± 10) colonies per 500 cells treated with an empty, no drug containing control gel (CS). To further assess CDDP accumulation to gDNA of tissues in vivo, inductively coupled plasma mass spectrometry (ICP-MS) was performed with tissue samples obtained from the left peritoneal sidewall of female nude mice following treatment with a control gel mixed with CDDP (CSCDDP), (CS(BCDDP)), and intravenously (i.v.) CDDP(CDDPIV). The results demonstrated a greater than three-time enhancement of CDDP-accumulation to the gDNA from (CS(BCDDP)) when compared to CDDPIV. Moreover, (CS(BCDDP)) also demonstrated higher accumulation of CDDP to gDNA when compared with CSCDDP. Relative values were 3.2 (±0.9) for (CS(BCDDP)) and 1.3 (± 0.4) for CSCDDP compared to values obtained from CDDPIV. Our in vitro and in vivo results, strongly suggest the feasibility of applying this hybrid gel locally to mucosal surfaces of the female reproductive tract and its advantage for intraperitoneal drug accumulation. Currently ongoing experiments are evaluating the efficacy and safety of our hybrid gel/CDDP in orthotopic endometrial, ovarian and cervical cancer animal models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1948. doi:1538-7445.AM2012-1948

Intraperitoneal antineoplastic drug delivery: experience with a cyclophosphamide, vincristine and prednisolone protocol in cats with malignant lymphoma

In this retrospective study, the efficacy and safety were examined for an intraperitoneal chemotherapy protocol-cyclophosphamide, vincristine and prednisolone (IP-COP) in 26 cats with malignant lymphoma. Certainly in cats fiercely resisting IV administration the IP route is a more practical method, safer for the administrator and less stressful for the cat. Complete remission (CR) rate was 76.9% (n = 20). Median duration of first remission was 421 days. Estimated 1- and 2-year disease free period were 67.1 and 48.0%, respectively. Median duration of survival was 388 days and estimated overall 1- and 2-year survival periods were 54.7 and 46.9% respectively. Young cats had a more favourable prognosis. Reaching CR was essential for long-term survival. No specific IP-related adverse events (AE) were seen. AE were generally scored as mild and were not excessively abundant. These results indicate that the IP route is a safe and effective alternative for the administration of COP protocol chemotherapeutics.

Pharmacokinetics and Pharmacodynamics of Intraperitoneal Cancer Chemotherapeutics

Peritoneal carcinomatosis remains a significant cause of morbidity and is a marker of poor prognosis in a range of malignancies, including those of the gastrointestinal and gynaecological tracts. In these cases, regional therapy has been explored as a treatment strategy to take advantage of the prolonged confinement of such tumours within the peritoneal cavity and the steep dose-response relationship for most cytotoxic agents. The pharmacokinetic rationale is based on exploiting the peritoneal-plasma barrier, which slows the rate of drug clearance from the peritoneal to systemic compartments and creates a concentration differential in favour of the peritoneal cavity. This allows higher drug concentrations, and thus increased cytotoxicity, to be achieved at the site of a tumour within the peritoneal cavity. There is pharmacodynamic evidence from a number of clinical trials to support the translation of these pharmacokinetic advantages of intraperitoneal chemotherapy into clinical benefit. However, its clinical application remains controversial because of concerns regarding intraperitoneal drug distribution, technical challenges and toxicity associated with regional drug delivery and the clinical relevance of the studies undertaken. The purpose of this review is to summarize the pharmacokinetic rationale of intraperitoneal drug delivery, review the pharmacodynamic studies performed in ovarian, colorectal and gastric cancers, and outline the future directions and challenges in the clinical application of this mode of treatment.

Description of a novel approach for intraperitoneal drug delivery and the related device

Description of a novel approach for intraperitoneal drug delivery and the related device

Current and Future Directions of Clinical Trials for Ovarian Cancer

The management of ovarian cancer includes a combination of surgery and chemotherapy. The majority of clinical trials have historically addressed questions pertaining to the selection, dosing, and schedule of chemotherapy agents. In this report, a comprehensive review of the major clinical trials in ovarian cancer is performed. The increasing data and clinical experience in the management of ovarian cancer, as it sets the stage for currently active protocols and future clinical trial design, are emphasized. Paclitaxel plus carboplatin is the primary intravenous treatment strategy in the front-line setting. Recent data show an improvement in overall survival for intravenous dose-dense treatment. Multiple randomized controlled trials support the use of intraperitoneal treatment. For recurrent disease, a growing number of new agents including targeted therapeutics are now available. Increasingly, surgical approach, biologic targets, and quality of life endpoints are included in clinical trial design. Over the last several decades, clinical trials have defined the current therapeutic approach for ovarian cancer. Paclitaxel with a platinum-based agent is currently the preferred front-line therapy, with encouraging data to support either dose-dense or intraperitoneal drug delivery. Future trials will determine the role of biologic agents and vaccine therapies, as well as their impact on quality of life.

The performance of expansile nanoparticles in a murine model of peritoneal carcinomatosis

Carcinomatosis from peritoneal surface malignancies, such as mesothelioma, appendiceal carcinoma or ovarian metastases, significantly decreases survival and quality of life. Given a 60–80% locoregional recurrence rate after surgical debulking for mesothelioma, the current study explores the use of polymeric nanoparticles, specifically engineered to expand and locally deliver chemotherapeutic agents at endosomal pH, for the prevention of progressive carcinomatosis. Anti-tumor efficacy of paclitaxel-loaded pH-responsive expansile nanoparticles (Pax-eNP) was evaluated in vitro and in in vivo murine models of malignant peritoneal mesothelioma. Pax-eNP inhibited mesothelioma growth in vitro, markedly decreased tumor growth and disease severity in vivo, prevented initial intraperitoneal tumor implants, and significantly prolonged survival compared to other intraperitoneal drug delivery methods. These outcomes suggest that the mechanism of pH-triggered drug delivery and tumor affinity associated with eNP may effectively improve the local control of residual microscopic disease following surgical debulking of locoregionally aggressive malignancies.

Drug Delivery Systems for Intraperitoneal Therapy

Disorders associated with the peritoneal cavity include peritoneal adhesions and intraperitoneal (IP) malignancies. To prevent peritoneal adhesions, physical barrier devices are used to prevent organs from contacting other structures in the abdomen and forming adhesions, or pharmacological agents that interfere with adhesion formation are administered intraperitoneally. IP malignancies are other disorders confined to the peritoneal cavity, which are treated by combination of surgical removal and chemotherapy of the residual tumor. IP drug delivery helps in the regional therapy of these disorders by providing relatively high concentration and longer half-life of a drug in the peritoneal cavity. Various studies suggest that IP delivery of anti-neoplastic agents is a promising approach for malignancies in the peritoneal cavity compared to the systemic administration. However, IP drug delivery faces several challenges, such as premature clearance of a small molecular weight drug from the peritoneal cavity, lack of target specificity, and poor drug penetration into the target tissues. Previous studies have proposed the use of micro/nanoparticles and/or hydrogel-based systems for prolonging the drug residence time in the peritoneal cavity. This commentary discusses the currently used IP drug delivery systems either clinically or experimentally and the remaining challenges in IP drug delivery for future development.

Large anti-HER2/neu liposomes for potential targeted intraperitoneal therapy of micrometastatic cancer

Effective targeting and killing of intraperitoneally disseminated micrometastases remains a challenge.Objective/Methods: In this work, we evaluated the potential of antibody-labeled PEGylated large liposomes as vehicles for direct intraperitoneal (i.p.) drug delivery with the aim to enhance the tumor-to-normal organ ratio and to improve the bioexposure of cancer cells to the delivered therapeutics while shifting the toxicities toward the spleen. These targeted liposomes are designed to combine: (1) specific targeting to and internalization by cancer cells mediated by liposome-conjugated tumor-specific antibodies, (2) slow clearance from the peritoneal cavity, and (3) shift of normal organ toxicities from the liver to the spleen due to their relatively large size.Results: Conjugation of anti-HER2/neu antibodies to the surface of large (approximately 600 nm in diameter) PEGylated liposomes results in fast, specific binding of targeted liposomes to cancer cells in vitro, followed by considerable cellular internalization. In vivo, after i.p. administration, these liposomes exhibit fast, specific binding to i.p. cancerous tumors. Large liposomes are slowly cleared from the peritoneal cavity, and they exhibit increased uptake by the spleen relative to the liver, while targeted large liposomes demonstrate specific tumor uptake at early times. Although tissue and tumor uptake are greater for cationic liposomes, the tumor-to-liver and spleen-to-liver ratios are similar for both membrane compositions, suggesting a primary role for the liposome’s size, compared to the liposome’s surface charge.Conclusions: The findings of this study suggest that large targeted liposomes administered i.p. could be a potent drug-delivery strategy for locoregional therapy of i.p. micrometastatic tumors.

Intraperitoneal therapy for peritoneal tumors: biophysics and clinical evidence

In patients with tumors confined to the peritoneal cavity, there is established pharmacokinetic and tumor biology-related evidence that intraperitoneal drug administration is advantageous. Three large randomized trials in patients with stage III ovarian cancer who underwent optimal cytoreduction have demonstrated a significant survival benefit when intraperitoneal chemotherapy was added to systemic therapy. Although intraperitoneal therapy is associated with locoregional toxic effects, recent trials suggest that with some modification of the local delivery methods this approach is safe in 80% of patients in an ambulatory setting. Surgical cytoreduction immediately followed by intraoperative hyperthermic intraperitoneal chemoperfusion (HIPEC) ensures intraperitoneal delivery of the drug to all peritoneal surfaces and the advantages of combined hyperthermia to be exploited. An increasing number of centers are initiating this multimodality therapy in ovarian cancer and colorectal cancer. Clearly, intraperitoneal drug delivery is an important adjunct to surgery and systemic chemotherapy in selected patients. The optimal drug, dose and schedule for intraperitoneal delivery, the exact role of added HIPEC compared with cytoreduction alone, and the potential role of HIPEC in ovarian cancer and peritoneal mesothelioma are still undefined. Several randomized controlled trials addressing these uncertainties have been initiated.

Mucinous Cancer of the Appendix: Challenges in Diagnosis and Treatment

The authors report and discuss a case of a mucinous carcinoma of the appendix, a rare entity with a distinct natural history that poses diagnostic and therapeutic challenges. Mucinous peritoneal carcinomatosis is most commonly associated with primary tumors of the appendix and colon. Typically, spread remains confined to the abdominal cavity. Imaging assessment of these mucinous lesions is difficult, while tumor markers (CEA and CA19.9) may be surrogates for extent of disease. Treatment consists of surgical debulking, sometimes coupled with intraperitoneal drug delivery, but recurrence is universal. New treatment approaches are needed. Mucin genes are regulated in part by epidermal growth factor receptor signaling. Therefore, we initiated a phase II study of cetuximab for mucinous peritoneal carcinomatosis, that was part of this patient's treatment.

Novel biocompatible intraperitoneal drug delivery system increases tolerability and therapeutic efficacy of paclitaxel in a human ovarian cancer xenograft model

We compared the safety, toxicity, biocompatibility and anti-tumour efficacy of a novel chitosan-egg phosphatidylcholine (ePC) implantable drug delivery system that provides controlled and sustained release of paclitaxel (PTX(ePC)) versus commercial paclitaxel formulated in Cremophor EL (PTX(CrEL)). Toxicity studies were conducted in healthy CD-1 female mice, whereas efficacy studies were performed in the SKOV-3 xenograft model of ovarian cancer. Treatments consisted of intraperitoneal (IP) implantation of drug-free or PTX(ePC) formulations, IP bolus PTX(CrEL), or Cremophor EL (CrEL) vehicle. Toxicity was assessed as number of deaths, weight loss, serum hepatic enzyme levels and histopathological changes. Mice implanted with drug-free or PTX(ePC) formulations did not exhibit observable toxicities, local inflammation or fibrous encapsulation of the implant. In contrast, mice receiving PTX(CrEL) or CrEL encountered significant toxicity, lethality, abnormal peritoneal organ morphology and hepatic inflammation. The maximum tolerable dose (MTD) of PTX(CrEL) was 20 mg/kg/week, whereas PTX doses of up to 280 mg/kg/week were well tolerated when administered as PTX(ePC). Enhanced anti-tumour efficacy was achieved with PTX(ePC) in contrast to PTX(CrEL) with the same total dose of 60 mg/kg PTX. The novel PTX(ePC) formulation is a safer and better tolerated method for PTX administration, with significant increase in MTD and enhanced anti-tumour efficacy, suggesting improved therapeutic index with possible clinical implications in the treatment of ovarian tumours.

Current and Future Directions of Clinical Trials for Ovarian Cancer

Background The management of ovarian cancer includes a combination of surgery and chemotherapy. The majority of clinical trials have historically addressed questions pertaining to the selection, dosing, and schedule of chemotherapy agents. Methods In this report, a comprehensive review of the major clinical trials in ovarian cancer is performed. The increasing data and clinical experience in the management of ovarian cancer, as it sets the stage for currently active protocols and future clinical trial design, are emphasized. Results Paclitaxel plus carboplatin is the primary intravenous treatment strategy in the front-line setting. Recent data show an improvement in overall survival for intravenous dose-dense treatment. Multiple randomized controlled trials support the use of intraperitoneal treatment. For recurrent disease, a growing number of new agents including targeted therapeutics are now available. Increasingly, surgical approach, biologic targets, and quality of life endpoints are included in clinical trial design. Conclusions Over the last several decades, clinical trials have defined the current therapeutic approach for ovarian cancer. Paclitaxel with a platinum-based agent is currently the preferred front-line therapy, with encouraging data to support either dose-dense or intraperitoneal drug delivery. Future trials will determine the role of biologic agents and vaccine therapies, as well as their impact on quality of life.

Clinical Efficacy Supporting the Role of Intraperitoneal Drug Delivery in the Primary Chemotherapeutic Management of Small-Volume Residual Advanced Ovarian Cancer

Delivery of chemotherapeutic agents directly into the peritoneum to treat tumors localized to the abdominal cavity is a concept tested initially in clinical practice in the early 1950s. However, thorough investigation of the drawbacks and potential of intraperitoneal (IP) drug administration was not explored until the late 1970s. After fading in popularity, three major phase III randomized trials (SWOG 8501/GOG 104, GOG 114, and GOG 172) have helped IP therapy to resurface as an acceptable alternative for selected stage III ovarian cancer patients with optimally debulked tumors. These trials have provided overwhelming evidence supporting the value of IP strategy in prolonging progression-free and overall survival rates. GOG 172 showed a remarkable 15.9 month increase in median overall survival for the IP arm in comparison to the intravenous arm. This review article discusses the clinical data available from these three Gynecologic Oncology Group (GOG) studies (SWOG 8501/GOG 104, GOG 114, and GOG 172), supporting the use of a combination of IP and intravenous chemotherapy in patients with stage III ovarian cancer after surgical debulking.

Phase II study of cetuximab in mucinous peritoneal carcinomatosis

14020 Background: Mucinous peritoneal carcinomatosis is most commonly associated with primariy tumors of the appendix and colon. Typically, spread remains confined to the abdominal cavity. Imaging assessment of these mucinous lesions is difficult, and tumor markers (CEA and CA19.9) are often used as a surrogate for extent of disease. Patients (pts) often undergo surgical debulking, sometimes coupled with intraperitoneal (IP) drug delivery, but recurrence is common. Since mucin genes are regulated by EGFR, our two institutions initiated this study. Methods: Between Sept 2004 and Dec 2005, weekly cetuximab (loading 400 mg/m2 on first dose, followed by 250 mg/m2/week thereafter) was given to 20 pts (4 men, 16 women): 17 of appendiceal origin were entered a median 3 y (6 m-7 y) after diagnosis; 3 were unknown primaries 24, 23, and 2 m after diagnosis. Prior treatment included surgery (18), systemic (17), and intraoperative (4) or subsequent IP therapy (2). Results: Pts received a median of 12 doses (0–51) of cetuximab. No major objective responses were observed; transient > 25% decreases in CEA and CA19.9 were noted in 4/19 pts; markers were never elevated in 1. Stable disease was best response in 3 of 15 evaluable (5 too early). The most common toxicities, as expected, were skin rash, dryness, and nail fragility. Hypersensitivity reactions in 2 patients did not preclude repeated dosing with premedications. The median time to progression from the start of treatment was 3 m. Conclusions: Brisk accrual by two institutions in this rare clinical entity is noteworthy. In this heavily pretreated population, transient decrease in tumor markers and time on study with stable disease were encouraging, prompting plans for a future study of cetuximab with the addition of systemic irinotecan. [Table: see text]

Point: Intraperitoneal Chemotherapy in the Management of Ovarian Cancer

Both preclinical considerations and results of phase I safety and pharmacokinetic studies provided support for the argument that intraperitoneal antineoplastic drug delivery should be a rational approach to the management of ovarian cancer. Subsequently conducted phase II trials exploring regional treatment revealed surgically documented objective responses when the approach was employed as a second-line therapy. Recently, the results of three randomized phase III trials have shown that the use of primary cisplatin-based intraperitoneal therapy leads to superior survival compared with intravenous cisplatin-based treatment in patients with small-volume residual advanced ovarian cancer after initial surgical cytoreduction. Further exploration of this unique management strategy is indicated to develop an optimal approach that maintains the demonstrated enhanced efficacy while reducing the toxicity (principally because of cisplatin) of treatment.

Cytoreductive Surgery Followed by Intraperitoneal Hyperthermic Perfusion in the Treatment of Recurrent Epithelial Ovarian Cancer: A Phase II Clinical Study

The optimal salvage therapy for recurrent ovarian carcinoma has not been clearly established. Response to second-line chemotherapy is low, with a short median survival (8.8-15 months). We investigated the effect of an aggressive approach consisting of surgery followed by intraperitoneal drug delivery and local hyperthermia. In a phase II clinical study, 27 patients with advanced/recurrent ovarian carcinoma were treated with cytoreductive surgery and intraperitoneal hyperthermic perfusion. Median patient age was 53 years (range, 30-67) and mean follow-up was 17.4 months (range, 0.3-36.0). Patients had been surgically staged and heavily pretreated with cisplatin-based, taxol-based or taxol/platinum-containing regimens. Nineteen (70%) patients were cytoreduced to minimal residual disease <2.5 mm. The intraperitoneal hyperthermic perfusion was performed with the closed abdomen technique, using a preheated polysaline perfusate containing cisplatin (25 mg/m2/L) + mitomycin C (3.3 mg/m2/L) through a heart-lung pump (mean flow of 700 mL/min) for 60 min in the hyperthermic phase (42.5 degrees C). Two-year overall survival was 55%. Median times to overall progression and local progression were 16 months and 21.8 months, respectively. Variables that affected the overall survival or time to progression were as follows: residual disease (P = 0.00025), patient age (P = 0.04), and lag time between diagnosis and cytoreductive surgery + intraperitoneal hyperthermic perfusion (P = 0.04). Treatment-related morbidity, mortality and acute toxicity (grade II-III) rates were 11%, 4% and 11%, respectively. Eight (89%) of 9 patients had ascites resolution. Our results suggest that cytoreductive surgery + intraperitoneal hyperthermic perfusion is a well-tolerated, feasible and promising alternative in the management of selected patients with recurrent ovarian cancer, but further randomized controlled studies are needed in order to confirm our findings.

Fluid Dynamics in Man of an Intraperitoneal Drug Delivery Solution: 4% Icodextrin

Interest in targeting drugs into the peritoneal cavity for intra-abdominal cancers or infections is undergoing a revival as recent clinical trials have demonstrated, not only a regional advantage in concentration of the active agent, but also improved long-term outcomes. Solutions currently used for intraperitoneal (IP) drug delivery have short residence times, however, which can limit the exposure of all areas of the peritoneum to the active agent. Icodextrin 4% solution was compared with saline and a glucose-based peritoneal dialysis solution in a clinical study of IP residence time. The study was carried out during the fortnightly rest phase in 9 patients undergoing 5-fluorouracil (5-Fu) IP treatment for colorectal cancer. The volume remaining in the peritoneal cavity was measured at 0, 12, 24, 48, 72, and 96 hr after an instillation of 2 liters of each fluid. Saline (n = 3 dwells) and glucose (n = 3 dwells) peritoneal dialysis solutions were almost fully absorbed by 24 hr, and the patients experienced discomfort when using these solutions. In contrast, icodextrin 4% solution (n = 188 dwells) maintained its instilled volume for up to 48 hr, and half the instilled volume remained after 72 and 96 hr. This result would allow extensive and prolonged coverage of the peritoneal surface. Icodextrin 4% solution may be an effective vehicle to deliver therapeutic agents into the peritoneal cavity.